Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

  • J Immunother Cancer. 2020 Dec;8(2):e001395. doi: 10.1136/jitc-2020-001395.
Julius Strauss  #  1 ,  Margaret E Gatti-Mays  #  1 ,  Byoung Chul Cho  2 ,  Andrew Hill  3 ,  Sébastien Salas  4 ,  Edward McClay  5 ,  Jason M Redman  6 ,  Houssein A Sater  6 ,  Renee N Donahue  1 ,  Caroline Jochems  1 ,  Elizabeth Lamping  6 ,  Andrea Burmeister  6  7 ,  Jennifer L Marté  6 ,  Lisa M Cordes  6 ,  Marijo Bilusic  6 ,  Fatima Karzai  6 ,  Laureen S Ojalvo  8 ,  Genevieve Jehl  9 ,  P Alexander Rolfe  8 ,  Christian S Hinrichs  6 ,  Ravi A Madan  6 ,  Jeffrey Schlom  1 ,  James L Gulley  10
Affiliations
  • 1. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • 2. Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 3. Tasman Oncology Research Ltd, Southport, Queensland, Australia.
  • 4. CEPCM Assistance Publique des Hôpitaux de Marseille; Aix-Marseille Université, Marseille, France.
  • 5. California Cancer Associates for Research and Excellence, Encinitas, California, USA.
  • 6. Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • 7. Leidos Biomedical Research, Frederick, Maryland, USA.
  • 8. EMD Serono Research & Development Institute, Inc, Billerica, Massachusetts, USA; an affiliate of Merck KGaA, Darmstadt, Germany.
  • 9. Merck KGaA, Darmstadt, Germany.
  • 10. Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA [email protected].
  • # Contributed equally.
PMID: 33323462 DOI: 10.1136/jitc-2020-001395
Abstract

Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β 'trap') fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa.

Methods: In these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; Other endpoints included safety.

Results: As of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar Cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred.

Conclusion: Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.

Keywords
programmed cell death 1 receptor.
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